Project Summary In order to develop better treatments for depression, there is a critical need to identify the key neurochemical events that drive changes in core depressive symptoms. Several agents have recently been shown to have more rapid effects than conventional antidepressants, suggesting that the sites of action of these novel agents are mechanistically closer to those key neurochemical events. Intravenous ketamine, in particular, has been shown to act within hours, and its efficacy has been confirmed in meta-analyses. Published work and preliminary data have led to the hypothesis that ketamine improves mood, interest, and hedonic tone by acutely enhancing neurotransmission within the brain's endogenous mu-opioid system. The proposed human mechanistic study will test this hypothesis by accomplishing two specific aims: (1) to demonstrate the acute effects of ketamine on endogenous mu-opioid neurotransmission; and (2) to determine the extent to which individual differences in ketamine-induced mu-opioid system activation are associated with changes in core depressive symptoms. These aims will be accomplished using positron emission tomography and the mu-opioid-specific radiotracer [11C]carfentanil in depressed patients receiving intravenous ketamine. This R21 exploratory project is expected to reveal, with neuroanatomical and neurochemical specificity, some of the key neural events that drive rapid changes in core depressive symptoms in humans. Identification of such neurochemical events is expected to spawn future studies that would determine whether changes in mu-opioid neurotransmission are necessary for symptom improvement (e.g., through pharmacological blockade) and whether reversal or loss of those neural changes accounts for the limited durability of the clinical effects of rapidly acting antidepressants. This work will have positive impact by advancing our understanding of those neural events that are necessary and sufficient to ameliorate depression, enabling more rational design of novel therapies. Thus the proposed research will ultimately advance the mission of the NIMH by reducing the burden of depression.